Asenapine or trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, was first described in U.S. Pat. No. 4,145,434 by van der Burg and is represented by a structure of Formula 1:

Asenapine is a broad-spectrum, high potency serotonin, noradrenaline and dopamine antagonist, which exhibits potential antipsychotic activity. Asenapine is marketed as its maleate salt for the treatment of schizophrenia and manic episodes associated with bipolar I disorders, in the form of sublingual tablets under the trademark SAPHRIS.
Pharmaceutical compositions comprising asenapine maleate for sublingual or buccal administration were first described in EP 0 746 317 B1. These sublingual tablets were prepared by a freeze-drying (lyophilisation) process. This process involves freezing off an aqueous-based drug solution followed by sublimation of the ice in a vacuum, an unworkable method for industrial applications.
As described in Funke et al., Arzneim.-Forsch./Drug Res., 40:536-539 (1990), asenapine maleate (Form H) was the first known polymorphic form. Form H is a monoclinic crystalline form having a melting point in the range of 141° C. to 145° C. EP 1 710 245 B1 and EP 1 917 267 B1 described the discovery of a new form of asenapine maleate (Form L), which is an orthorhombic crystalline form having a melting point in the range of 138° C. to 142° C. EP 1 710 245 131 and EP 1 917 267 B1 mention the importance of asenapine particle size since asenapine commercial sublingual tablets are dissolved in the mouth. Thus, particles having a size distribution characterized by a d95 (95% volume of the particles are smaller than or equal to the indicated size) of about 100 μm or less, more preferably about 50 μm or less, and even more preferably about 30 μm or less, is desirable for sublingual formulations. According to EP 1 710 245 B1 and EP 1 917 267 B1, the outcome of the micronisation process used therein, and which is necessary to reduce the particle size of crystals, appeared to be unpredictable when crystals of monoclinic form of asenapine maleate were subjected to the micronisation process. Crystals of the orthorhombic form were found to be present in addition to the known monoclinic form in the starting material. The present inventors have also observed that micronisation of the crystals of the monoclinic form of asenapine maleate, prepared as disclosed in U.S. Pat. No. 4,145,434, were not stable and eventually evolved to the orthorhombic crystalline form. On the contrary, micronisation of the orthorhombic crystalline form of asenapine maleate disclosed in EP 1 710 245 B1 and EP 1 917 267 B1 reproducibly resulted in asenapine maleate of the orthorhombic crystalline form comprising particles having a size distribution characterized by a d95 of 30 μm or less. The preparation process of the orthorhombic form of asenapine maleate described in EP 1 710 245 B1 and EP 1 917 267 B1 comprised a very long crystallization step (between 42-72 hours), unlike the crystallization of monoclinic form of asenapine maleate (about 3 hours), which makes the preparation of orthorhombic crystalline form of asenapine maleate of low particle size an economically disadvantageous procedure.
In accordance with regulatory requirements of the U.S. and other countries, e.g. the FDA's Good Manufacturing Practice (“GMP”) requirements, when preparing pharmaceutical compositions containing active ingredients for administration to mammals, there is a need to produce crystalline forms, or polymorphs, which are as pure and as stable as possible. Differences in the chemical and physical properties of polymorphic forms of an active ingredient such as melting point, chemical reactivity and apparent solubility can have a direct effect on the ability to process and/or manufacture the active ingredient and its pharmaceutical compositions, as well as on its stability, dissolution and bioavailability. Thus, a process that provides an unstable polymorphic form is not desirable.
Therefore, it is desirable to develop a feasible preparation method to produce polymorphically stable asenapine maleate of low particle size, such that it is suitable for the preparation of sublingual pharmaceutical compositions of asenapine maleate.